Some of the information set forth herein has been published (see Masao Koyama, T. Ross Kelly and Kyoichi A. Watanabe, Novel Type of Potential Anticancer Agents Derived from Chrysophanol and Emodin). Some Structure-Activity Relationship Studies, Journal of Medicinal Chemistry, 1988, 31: 283-284, which was distributed by the publisher on Jan. 29, 1988.
Certain antitumor intercalating agents, e.g., ellipticine, m-AMSA and anthracycline antibiotics, have been the subject of structural modifications in order to gain better therapeutic potential. A number of analogs of ellipticine [LePeck, J. B., et al., Proc. Natl. Acad. Sci., U.S.A., 71: 5078 (1974); Guthrie, R. W., et al. J. Med. Chem., 18: 755 (1975)], m-AMSA [Denny, W.A., et al., J. Med. Chem., 25: 276 (1982)] and anthracycline antibiotics [Mosher, C. W., et al., J. Med. Chem., 25: 18 (1982); Seshadri, R., et al., J. Med. Chem., 26: 11 (1983); Li, L. H., et al., Cancer Res., 42: 999 (1982)] have been synthesized and screened for their anticancer activity. Unfortunately, however, preliminary screening data show that there is no straightforward structure-activity relationship between intercalating potency and anticancer activity.
These results seem to suggest that though intercalation may be a necessary condition, it may not be sufficient for such a drug to exert anticancer activity.
Recent studies on the mechanism of anticancer action of antibiotic CC1065 [Chidester, C. G., et al., J. Am. Chem. Soc., 103: 7629 (1981); Kanatomo, S., et al., Chem. pharm. Bull., 29: 229 (1981)] show that it binds to the minor groove of DNA by non-intercalative means and then slowly alkylates the amino group of adenine by opening the cyclopropane ring in the antibiotic molecule. With CC1065, covalent binding of the drug with DNA, therefore, seems to be important for its potent cytotoxic activity. Mere physical interaction between the drug and DNA may not be sufficient.
These considerations point to the development of intercalators with slow alkylating capability. Such intercalators will bind covalently and hopefully should eventually disrupt the DNA function.
The compounds of the present invention have both intercalating and alkylating functionalities, and as such are potential anticancer agents.
The compounds of this invention may also be useful as biochemical probes for biological reactions essential for DNA synthesis.